21-chloro steroids



United States Patent ZI-CHLORO STEROIDS Josef Fried and Josef E. Herz, New Brunswick, N.J., assignors to 01in Mathieson Chemical Corporation,

New York, N.Y., a corporation of Virginia No Drawing. Original application June 4, 1954, Serial 5 No. 434,672, now Patent No. 2,763,671, dated September 18, 1956. Divided and this application April 16, 1956, Serial No. 582,314

3 Claims. (Cl. 260-397.3)

This application is a division of our parent application, Serial No. 434,672, filed June 4, 1954, and now Patent No. 2,763,671, granted September 18, 1956.

This invention relates to the synthesis of valuable steroids; and has for its objects the provision of (I) an advantageous process of preparing steroids of the pregnane (including the pregnene and allopregnane) series having a 9a-halogen substituent and an ll-keto or 11,8-hydroxy substituent, and of (II) certain compounds useful themselves as physiologically-active steroids and in the preparation of other physiologically-active steroid derivatives. i

(The process of this invention essentially comprises (a) converting an 11a,21-dihydroxy steroid of the pregnane series into the corresponding 11a,21-di(alkanesulfonyloxy) or 11a-alkane-sulfonyloxy-2l-chloro derivatives thereof, (b) converting the latter into the cone spending A -21-chloro derivative, (0) converting said A9(11) ,compound into the corresponding 9a-bromo or chloro, llfi-hydroxy derivative, (d) converting said 9p:- bromo or chloro compound to the corresponding 9 8,115- oxido,2l-chloro derivative, and (e) converting said 913,- llfi-oxido derivative to the corresponding 9a-halo,11flhydroxy compound.

The compounds of this invention comprises: A ,21- chloro steroids of the pregnane series.

For a clearer understanding of the foregoing general and following detailed description of one of the related processes of this invention, reference is made to the following schematic analysis:

CHaOH wherein the 4,5 position is double-bonded or saturated (the 4,5-double-bonded steroids are preferred), and wherein R is hydrogen, R is hydroxy, or together R and R is oXo (keto) or a group convertible thereto by hydrolysis (e.g'. ketal), R and R' as 0x0 being preferred; Z is hydrogen or a-hydroxy; R" is an alkanesulfonyl radical, particularly a lower alkane sulfonyl such as methane-sulfonyl, ethanesulfonyl, hexanesulfonyl, etc., and is preferably methanesulfonyl; X is chloro, bromo, or iodo; R'." is R"O or chloro; Me is a metal,'such as an alkali metal oran alkaline earth metal, the halogen salt of which is soluble in the solvent employed in the indicated reaction, preferably an alkali metal, such as sodium or lithium; Y is hydrogen, bromo, or chloro; RX' is an N-bromamide (including imide) of a carboxylic acid (including derivatives), an N-chloramide (including imide) of a carboxylic-acid (including derivatives), dibromodimethylhydantoin, or dichlorodimethylhydantoin; X is bromo or chloro; Y is acetoxy or chloro; and X" is a halo (fiuoro, chloro, bromo, or iodo).

Compounds suitable as initial reactants in the process of this invention set out in the foregoing schematic analysis include compound epi-F (A -pregnene-11u,17a,21- triol-3,20-dione'), epi-corticosterone A -pregnene-llalldiol-3 ,ZO-dione) 1 1oz, 17u,2 l-trihydroxy-pregnane-3,ZO-dione, 11a,21-dihydroxypregnane-3,20-dione, etc. These compounds are reacted with alkanesulfonyl halides (sulfonyl chlorides are preferred but other halides such as bromides and iodides may be used). Although any alkanesulfonyl chloride may be used, the alkane group is preferably a lower alkane, methanesulfonyl chloride (mesyl chloride) being particularly preferred. The reaction is carried out in accordance with the general method disclosed in the US. application of Josef Fried, Serial No. 417,489, filed March 10, 1954, now Patent No. 2,852,511 granted September 16, 1958, and in the following examples, by reacting the steroid and sulfonyl halide in the presence of dry pyridine or other tertiary organic base.

This reaction results in the production of compounds A wherein the alkanesulfonyloxy radical in the Ila-position corresponds to the alkanesulfonyl halide used in the reaction and the radical in the 21-position also corresponds to the alkanesulfonyloxy radical if Z is a-hydroxy, and is a mixture of steroids having the corresponding 21- alkanesulfonyloxy radical and steroids having a 2l-chloro radical if Z is hydrogen.

Compounds A are then reacted with a metal halide (MeX) wherein MeX is as above-defined. Particularly preferred metal halides are lithium chloride, lithium bromide and sodium iodide.

Other utilizable salts include beryllium chloride, calcium chloride, potassium bromide, calcium bromide, and barium bromide. The reaction is carried out-tin the presence of at least one mole/ mole of steroid of an alkali metal salt of a weak acid, such as an alkali metal lower Patented June 30, 1959 alkanoate (preferably sodium acetate), an alkali metal carbonate, an alkali metal bicarbonate, etc. The reaction is conducted in a suitable solvent wherein both the metal halide and alkali metal salt of the weak acid are soluble.

Such solvents include the lower alkanoic acids (particularly glacial acetic acid), certain alcohols, and ketones.

This reaction results in the production of compounds B wherein the 2l-substituentis: bromine when a metal bromide is used; chlorine when a metal chloride is used; and hydrogen when a metal iodide is used (the intermediately formed 21-iodo derivative having been reduced).

Compounds B are then reacted with R"X', wherein R""X' is as above-defined, and is preferably N-bromoacetamide, Nbromosuccinimide, N-chloroacetamide, N- chlorosuccinimide, dibromodimethyl hydantoin, or dichlorodimethyl hydantoin, in accordance with the method disclosed in the copending applications of Fried, Serial No. 417,489, filed March 10, 1954, and Fried et al., Serial No. 429,108, filed May 11, 1954. As disclosed in those applications, the conversion is preferably effected in the presence of perchloric acid or other relatively strong acids. This reaction produces compounds C having a 9u-chloro or bromo substituent and an llfl-hydroxy radical.

Compounds C are then reacted with alkali metal acetates such as potassium acetate, in a suitable solvent such as alcohols, lower alkanoic acids, or ketones (preferably in an alkanol such as ethanol) as described in the aforementioned application Serial No. 417,489.

By this reaction, compounds D are formed having a 9fl,ll;8-oxido radical, and a 21-substituent which is: hydrogen when the 21-substituent of compounds C is hydro gen; acetoxy, when the 2l-substituent of compounds C is bromo; and chloro, when the 2l-substituent of compounds C is chloro. In the case where the 21-substituent of compounds C is chloro, by reacting compounds C in the presence of an alkali metal iodide (e.g. potassium iodide) as well as the alkali metal acetate (e.g. potas sium acetate), the 2l-substituent in compounds D obtained is an acetoxy rather than a chloro radical.

Compounds D are then reacted with hydrogen halide (i.e. hydrofluoric, hydrochloric, hydrobromi'c, or hydroiodic acid) in a suitable solvent (e.g. chloroform) as disclosed in the aforementioned application Serial No. 417,489. By this reaction, compounds E are formed having a 9oc-h3l0 and llfi-hydroxy radical and a 21- substituent corresponding to the substituent in compounds D. The process of this invention is described in detail in the following schematic analysis and examples employing compound epi-F as a starting material, but is of course not limited thereto:

Example 1.-A -pregnene-11a,]7a,21 trial 3,20 dione 11a,21-dimesylate (I) (epi-F 11a,2]-dimesylate) To a solution of 10 g. epi-F in 110 ml. anhydrous pyridine is added at 0 C. (all temperatures given hereinafter being in centigrade) a solution of 6.6 ml. methanesulfony chloride in 10 ml. chloroform. The reaction mixture is allowed to remain at 0 for fifteen hours, after which 1 g. of ice is added. After an additional one-half hour at 0, the mixture is concentrated in vacuo to a small volume. The resulting residue is taken up in chloroform and water, and the chloroform solution is washed with cold dilute hydrochloric acid, dilute sodium bicarbonate solution, and finally with water. The chloroform solution is then dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue (about 12.4 g.) is recrystallized from ethanol, yielding the analytically pure dimesylate, having the following properties: M.P. about 162 (dec.); [a] +97 (c., 0.98 in dioxane); analysis [calculated for C H O S (502.62): C, 53.26; H, 6.60; S, 12.36; found (approximately): C, 53.42; H, 6.29; S, 11.00].

Example 2.-21-chl0r0=A -pregnene-11a ol 3,20-di0ne 11 a-mesylate and epicorticosterone dimesylate 238 m;1.(e=l6,650), $32 5.81 u, 6.04 ,4, 6.23

Analysis.-Calcd. for C H O SCl (442.99): C, 59.65; H, 7.05; S, 7.24; Cl, 8.00. Found: C, 59.19; H, 6.91; S, 8.52; Cl, 7.78.

The material recovered from the mother liquor constitutes the l1u,2l-dimesylate of epicorticosterone.

The following three examples illustrate the preparation of A -preguene derivatives of this invention.

Example 3.21 homo-A -pregnadiene-1 7a-ol-3,20- dione (II) A solution of 100 mg. of epi-F dimesylate (I) (prepared as in Example 1), 25 mg. of anhydrous potassium acetate and 200 mg. of anhydrous lithium bromide in 6 ml. of glacial acetic acid is refluxed with the exclusion of moisture for 1 hour. The slightly colored solution is then evaporated to dryness in vacuo. The residue is taken up in chloroform and water and washed with NaHCO and again with water. The dried chloroform solution is evaporated leaving a crystalline residue which weighs about 76 mg. Recrystallization from acetone gives prisms M.P. 198199 (dec.), about 48 mg.; M.P.

191-192 (dec.). about 13 mg.,- 181 4-106 (c., 0.56 in chloroform) yield: about 75%.

R512 239 m (6=16 400 280 m" =995 2.97

I: 1 )2 )1 #1 'Analysis.-Calcd. for c rr o sr 407.35): 0, 61.91;

H, 6.68; BI, 19.62. Found: C, 61.79; H, 6.73; B1, 19.59.

Example 4.-A pregnadiene-I 7 01-21 -dil-3,20-di0ne 21 -acetate A solution of 21 mg. of 21-bromo-A -pregnadiene- 1701-01-330-(110116 (II) and 125 mg. of anhydrous potassium acetate in 5 ml. of absolute ethanol is refluxed for one hour. The solvent is removed in vacuo, the residue taken up in water and chloroform and the chloroform solution washed several times with water. Evaporation of the solvent yields about 35 mg. of a crystalline solid, which after recrystallization from acetone aflords about 14 mg. of A -pregnadiene-17a,21-diol-3,20-dione 21- acetate, disclosed in the aforementioned application Serial No. 417,489.

Example 5.--21 chlora-A -pregnadiene-I7u-ol-3,20- dione (111) dioxane layer washed with bicarbonate and water. After drying and evaporation of the solvents in vacuo an oil is obtained which crystallized on addition of ether. The

- crystals are leached with more ether, and dried, M.P.

A solution of 100 mg. of epi-F dimesylate (I), mg. J

of anhydrous potassium acetate and 200 mg. of lithium chloride in 6 ml. of glacial acetic acid is refluxed for 1 hour with the exclusion of moisture. The acetic acid is removed in vacuo, the residue taken up in chloroform and water and the chloroform solution washed with bi- Analysis.Calcd. for c,,H,,0,c1 (362.89): C, 69.50; H, 7.50; Cl, 9.77.- Found: C; 69.94; H, 7.72; Cl, 9.75.

Example 6.A -pregnadiene-17a-ol-3,20-dione (IV) A solution of 100 mg of epi-F dimesylate (I), 25 mg.

of anhydrous potassium acetate and 400 mg. of sodium iodide in 6 m1. of glacial acetic acid is refluxed for minutes. The solution soon assumes the brown iodine color. At the end ofthe reaction time the acetic acid is removed in vacuo, the residue taken 'up in water and chloroform a'ndjthe chloroform solution washed with sodium sulfite solution and water. After drying over sodium sulfate and evaporation of the solvent in vacuo, about 63 mg. of crystals (93%) are obtained. 'Recrystah lization from acetone yields about 43 mg. of pure A -pregnadiene-17a-ol-3,20-dione, M.P. 216-217", '[a] +63 (c., 0.39 in chloroform). Infrared compari- 'son shows identity with an authentic sample.

Following the procedure of Example 6 with the 21- chlor'o-lla-hydroxyprogesterone lla-mesylate of Example 2 substituted for epi-F dimesylate, 21-chloro-A pregnadiene-3,20-dione is produced.

The following examples illustrate the preparation of the 9a-halo,11,B-hydroxy pregnane derivatives in accordance with this invention: t

Example 7.-9a,2 l-dibror n0 A4 pregnene-I 70:,11/8-dibl- 3,20-dione (V) 901,21 dibrom0-I1fl,17u-dihydroxypro- I gesterone] 1 148150 (dec.), about 237 mg. (77%). A sample is recrystallized twice from acetone-ether, M.P. 169-170 (dec.), ;+161(c., 0.39 in EtOH), 1332 2 12 m (6 17,400), 8,32 3.01 p, 5.79 .t, 6.10 11..

Analjsia-Calcd. for C H O Br (504.27): C, 50.02; 11,5.60; Br, 31.70. Found: C, 50.68; H, 5.88; Br, 30.09.

Example 8.9a bromo-21 -chlaro-A -pregnene-1 1 5,1 701- di0l 3,20 dione (VI) [9u-br0m0-21willow-115,170:-

dihydroxy-progesterone] To a solution of 100 mg. of 2l-chloro-A -pregnadiene-17a-ol-3,20-dione (III) in 10 ml. of dioxane and 1 ml, of water is added 56 mg. of N-bromoacetamide and 0.65 ml. of 1 N HClO The solution was stirred for 1% hours and the excess N-bromoacetamide is destroyed by the addition of a dilute sodium sulfite solution. After the addition of 30 ml. of chloroform the resulting layers are separated and the chloroformdioxane phase washed with water, NaHCO and again with water, dried over sodium sulfate and evaporated in vacuo. An oil is obtained which crystallized on addition of acetone-ether. About 78 mg. of crystals of M.P. 2l2-215 (dec.) are obtained. The mother liquors contain an additional 47 mg. The analytical sample is recrystallized from acetone-ether, M.P. 2l8219 (dec.), [eth l-175 (c., 0.36 in chloroform,

mg? 243 111,. $15,900), m... 3 04 a, -8 a, u

1 AnaIysis.-Calcd. for C H O BrCl (459.81): C, 54.85; H, 6.14; Br, 17.38. Found: C, 54.83; H, 6.02; Br, 18.34.

If Example 7 is repeated with dichlorodimethylhydantoin substituted for N-bromoacetamide, 9a-chloro,21- bromo-A -pregnene 11p,l7a diol 3,20 dione (VII) [9a-chloro,21 bromo 1113,1701 dihydroxyprogesterone] is produced.

' If Example 8 is repeated with dichlorodimethylhydantoin substituted for N-bromoacetamide, 911,21-dichloro-A pregnene 1118,1701 diol-3,20-dione (VIII) [901,21 dichloro 113,170: dihydroxyprogesterone] is produced.-

Example 9.---t bromo-M-p'regnene-Il [3,1 7oz diol-3,20- dione (IX) 330 mg. of A -pregnadiene 170c-01-3,20 dione (IV) is treated with 200 mg. N-bromoacetamide, and the reaction mixture worked up as described in Example 7. The resulting crude product (about 450 mg.) is recrysallized from acetone-chloroform, and yields about 362 mg. (85%) pure 9oz bromo-1113,17a,dihydroxyprogresterone, having the following properties: M.P. about 189-191 (dec.); [a] 128 (c., 0.33 in chloroform);

m1; 243 m;1(e=16,700); xgggaass ,1 (OH), 5.86 .1 (20- ketone), 6.04 p, 6.08 ,a (A -3-ketone) analysis [calculated for C H O Br (425.36): C, 59.29; H, 6.87; Br, 18.79; found (approximately): C, 59.59; H, 6.81; Br, 18.61].

Example 10.9a chloro A pregnene 11fi,17a-di0l- 3,20 dione (X) [900 chloro 1113,1701 dihydroxyprogresterone] 110 mg. of A -pregnadiene-17u ol 3,20-dione (IV) is dissolved in 20 ml. of dioxane and 2 ml. of water is added To the resulting solution is added mg. of N,N-dichlorodimethylhydantoin and 1 ml. of 1 N perchloric acid and the mixture is allowed to stand at room temperature for 30 minutes. Dilute aqueous sodium sulfite solution is added to destroy residual N,N-dichloro dimethyl hydantoin and the mixture is diluted with 25 ml. of chloroform which causesseparation into two layers. The chloroform-dioxane phase is separated oif, washed with water, sodium bicarbonate and again with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue (about 128 mg.) on recrystallization from ace.one-chloroform-hexane yields pure 90c chloro 11p,17a-dihydroxyprogesterone, M.P. about 242-243 C. (dec.). The compound is identified by infrared spectrum and mixture melting point comparison with an authentic sample. Yield about 58 mg.

If 2l-chloro-A -pregnadiene 3,20 dione is substituted for compound IV in Examples 9 and 10, 21- ChlOI'O-9oc bromo A pregnene 11B ol 3,20-dione [21 chloro 9a bromo 115 hydroxyprogesterone] and 9a,21 dichloro A pregnene 1113 ol-3,20-dione [9a,21 dichloro 11p hydroxyprogesterone] are formed, respectively.

The following examples illustrate the preparation of 913,11fi-oxido pregnane derivatives in accordance with this invention.

Example ]1.--9fi,11f3 oxido A pregnene 170:,21- diol-3,.20-dine 2l-acetaze (XI) A solution of 180 mg. of 9a,21-dibromo-A -pregnene- 170:,115-di0l 3,20 dione (V) and 500 mg. of anhydrous potassium acetate in 25 ml. of absolute alcohol is refiuxed for 2 /2 hrs. The ethanol is removed in vacuo and the resulting residue taken up in Water and chloroform and the chloroform solution washed free of salts. After drying and evaporation of the chloroform about 155 mg. of crystalline material are obtained. Recrystallization from acetone-ether affords about 50 mg. of pure material M.P.' 207209 and about 17 mg. of MP. 195-196 (47%), [a] +30 (c., 0.41 in chloroform). Infrared comparison showed identity with authentic 95,11,8-oxido- A -pregnene 170:,21 diol 3,20 dione Zl-acetate (cf. the aforementioned application Serial No. 417,409).

Example 12.-21 chloro 919,113 oxido-M-pregnene- 17cc ol 3,20 dione (XII) The process of Example 11 is repeated with 9a-bromo- 2l-chloro-A -pregnene 116,170: diol 3,20 dione (VI) substituted for 90,2l dibromo A -pregnene 170:,115- L Example 13.-21 chloro 95,1118 oxido-A -pregnene- 3,20-dione The process of Example 11 is repeated with 21-chloro 9a bromo A -pregnene 11/3-ol-3,20-dione substituted for 90:,21 dibromo A -pregnene-17a,11/3-diol-3,20- dione (V). After isolating and purifying in accordance with the method of Example 11, 21-chloro-9B,11p-oxido- A -pregnene-3,20-dione is obtained.

95,1118 oxido-A -pregnene-17a,21 diol .3,20-dione 21-acetate (XI) may be converted to 9u-halo-A -pregnene- 11B,17a,21 triol 3,20 dione wot-halohydrocortisone) and its 21-acyl derivatives (e.g., 9oz halohydrocortisone acetate) as Well as the corresponding 90: halo A pregnene 170a,21 diol 3,11,20 trione (9a halocortisone) and its 21 acyl derivatives (e.g., 9oz-hal0- cortisone 21-acetate) by the method disclosed in the aforementioned application Serial Number 417,489.

21-chlor0-9,B,11[3 oxido-A' pregnene 17a ol 3,20- dione (XII) similarly may be converted to the corresponding 21-chloro-9u halo-A pregnene l1fi,l7u-di0l- 3,20 dione as well as 21-chloro-9ot-halo-A pregnene-17mol-3,11,20-trione, which are new steroids having mineralo and glucocorticoid activity; and 21 ch1oro- 9;8,11}8 -oxido- A -pregnene 3,20 dione may also be converted to the corresponding 21-chloro -9a' halo A pregnene -01- 3,20-dione as well as 21-chloro-9m-halo M-pregnene-Ii,1'1, 20-trione, which are new steroids having mineralocorticoid activity.

A second process related to the process of this invention is shown in the following schematic analysis:

=0 110$: CHiCOOMe x' -----v' a wherein the 4,5 position is double-bonded or saturated (the 4,5-double-bonded steroids being preferred), and wherein R is hydrogen, R is hydroxy, or together R and R is oxo (kcto) or a group convertible thereto by hydrolysis (e.g. ketal) (R and R as oxo being preferred); Z is hydrogen or a-hYdI'OXY; R""X' is N-bromoamide (including horde) of a carboxylic acid (including derivatives), dibromodimethylhydantoin, or dichlorodimethylhydantoin; X, therefore, being bromo or chloro; Me is a metal and preferably an alkali metal such as sodium or potassium.

Compounds suitable as initial reactants in the foregoing process of the invention include:'A pregnadiene- ;,21-diol-3,20-dione; A -pregnadiene-21-ol-3,20-dione; A -pregnene-17u,21-diol-3,20-dione; M -pregnene-21-ol-3,20-dione, etc. These comounds are reacted with a hydroxychlorinating or hydroxy-brominating agent (R"X', wherein R""X? is as above-defined), and preferably N-bromoacetamide (or other N-bromo-lower alkanoic acid amide), N-hromosuccinimide, N-chloroacetamide (or other N-chloro-lower alkanoic acid amide), N- chlorosuccinimide, dibrornodimethylhydantoin, or dichlorodimethylhydantoin, in accordance with the method disclosed in'the copending applications of Fried, Serial No. 417,489, filed March 10, 1954; and Fried et al., Serial No. 429,108, filed May 11, 1954. As disclosed in those applications, the conversion is preferably effected in the presence of perchloric acid or other relatively strong acid. This reaction produces compounds F having a 9oz-chl0r0 or bromo substituent and an lfl-hydroxy radical.

Compounds F are then reacted with metal acetates, preferably alkali metal acetates such as potassium acetate, in a suitable solvent such as alcohol, a lower alkanoic acid, or a ketone (preferably in an alkanol such as ethanol) as described in the aforementioned application Serial No. 417,489. By this reaction, compounds G, having a 918,11fi-oxido radical,'are formed. Compounds G may then be reacted as disclosed in Serial No. 417,489 to produce 9a-ha'lo, llfi-hydroxy derivatives.

' This process is described in detail'in the following schematic analysis and examples in connection with the use of A -pregnadiene-17a,21-diol-3,20-dione as a starting material, but is of course not limited thereto:

( 213,011 :0 ---orr Example 14.9a-br0m0-A -pregnene-1 119,1 7a,21-tri0l-3, 20-dione (XV) To a solution of A -pregnadiene-17a,21-diol-3,20- dione, M.P. 237-240, in 30 ml. of dioxane is added ml. of Va N perchloric acid and 160 mg. of N-bromoacetamide. The solution is stirred for 1% hours, then 8 ml. of Na SO solution is added. The solution is diluted with 30 ml. of water and extracted with four portions each of 30 m1. of chloroform. The combined chloroform extracts are washed with water, sodium bicarbonate and again with water, dried over Na S0 and concentrated to dryness in vacuo. The semisolid residue is suspended in 5 ml. of hot ethyl acetate and filtered. The resulting crystals (about 175 mg., carbonization at 140-150) on repeated crystallization from ethyl acetate furnish about 30.2 mg. of material, carbonization at 128-135, [a] +166.7 (in 95% ethanol) A323 242 m (e= 16,800)

Analysis.Calcd. C I-I O Br (441.26): C, 57.14; H, 6.62; Br, 18.11. Found: C, 57.67; H, 6.89; Br. 18.27.

By substituting dichlorodimethylhydantoin for the N- bromoacetamide of the above example, 9a-chloro-A -pregnene-l1p,17a,21-triol-3,20-dione (XVI) is formed in the same manner.

Example 15.A pregnene 913,115 oxz'do 17a,21-diol- 3,20-di0ne (XVII) To a solution of 25 mg. of potassium acetate and 0.02 ml. of pyridine in 7 ml. of absolute ethanol is added 31 mg. of 9a-bromo-A -pregnene-1113,17a-21-triol-3,20-dione (XV). The resulting solution is refluxed for 40 minutes,

cooled down to 7, 25 ml. of water are added and the cold opalescent solution extracted with 3 portions of 20 ml. of ethyl acetate. The ethyl acetate extract is washed with water, dried over Na SO and concentrated to dryness in vacuo. Repeated recrystallizations give about 6 mg. of A -pregnene-9p,11fi-oxido-17a,21-di0l-3,20-dione, M.P. 211-213". The identity of this compound was established by infrared comparison with an authentic sample.

Compound XVII may also be formed from the cchloro analog (Compound XVI) by substituting the 9mchloro-compound for the 9a-bromo derivative.

The invention may be otherwise embodied within the scope of the appended claims.

We claim: 1. A compound selected from the group consisting of:

=0 1.--.z EC and r O -Ql wherein R is selected from the group consisting of keto and ketal; and Z is selected from the group consisting of hydrogen and hydroxy.

2. 21-chloro-A -pregnadiene-17a-ol-3,20-dione.

3. 21-ch1oro-A -pregnadiene-3,20-dione.

References Cited in the file of this patent UNITED STATES PATENTS 2,409,798 Reichstein Oct. 22, 1946 2,666,070 Murray et a1. Ian. 12, 1954 2,681,919 Levin et a1 June 22, 1954 2,684,968 Bergstrom July 27, 1954 2,703,799 Bergstrom Mar. 8, 1955 2,707,190 Farrar Apr. 26, 1955 2,712,028 Rosenkranz June 28, 1955 2,730,525 Hogg et a1. Jan. 10, 1956 2,734,897 Chemrda Feb. 14, 1956 2,736,734 Sarett Feb. 28, 1956 2,773,080 Bernstein Dec. 4, 1956 UNITED STATES PATENT OFFICE (Jertificate of Correction Patent No. 2,892,850 June 30, 1959 Josef Fried et 211.

It is hereby certified that error appears in the printed speeificetion of the above numbered gatent requiring correction and that the said Letters Patent should read es correcte below.

. Column 3, lines 52 to 62 inclusive, right-hand portion of the formula should appear as shown below instead of as in the patent:

omosmcm I column 8, line 63, for lfl-hydroxy read --11,B-hydroxy-.

Signed and sealed this 10th day of November 1959.

Attest:

KARL H. AXLINE, ROBERT C. WATSON,

Attestz'ng Oficer. Gamm'ssiomr of Patents. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: 